Anaphylaxis management in a French pediatric emergency department: Lessons from the ANA‐PED study

Abstract Background Anaphylaxis is a serious systemic hypersensitivity reaction that requires immediate recognition and prompt administration of epinephrine/adrenaline. The present study aimed to assess the appropriateness of epinephrine/adrenaline use in children identified as allergic by physicians in the emergency department (ED) at the time of the reaction, and to identify factors that are possibly associated with epinephrine/adrenaline administration, auto‐injector prescription, and further referral to an allergist. Methods We performed a retrospective cross‐sectional study at the pediatric ED of the University Hospital of Montpellier, France. We included all consecutive children who attended the ED between 2016 and 2020 with an allergy‐related diagnosis at discharge. Results We included 1056 allergy‐related visits, including 224 (21.2%) with a diagnosis of anaphylaxis at discharge; only 17.0% of them received an epinephrine/adrenaline injection, and 57.1% consulted an allergist after the acute episode. An auto‐injector was prescribed to 63 (28.1%) patients at discharge from the ED. Besides the severity of the clinical presentation, factors associated with a guidelines‐based management of the anaphylactic reaction and with an increased administration rate of epinephrine/adrenaline included presence of asthma symptoms and presence of extended skin reactions. Conclusions Our study underlines persistent gaps in the management of pediatric anaphylaxis in ED, focusing on hereby identified levers. By disseminating current knowledge and guidelines on anaphylaxis and allergies, specialists could work together with emergency physicians to establish effective management algorithms and improve anaphylaxis management and care pathways for children experiencing allergic reactions, especially anaphylaxis. Trail Registration Clinical Trials, number NCT05112367.


| INTRODUCTION
Anaphylaxis is a serious systemic hypersensitivity reaction, mainly appearing with a rapid onset and being potentially life-threatening, possibly compromising the respiratory and cardio-circulatory systems. 1,2 Its definition has evolved over the past years and has been simplified by multiple publications on this subject [1][2][3][4] to avoid capturing severe cases only. In 2020, the World Allergy Organization (WAO) defined anaphylaxis as an allergic hypersensitivity reaction involving at least two organs, without the need for patients to present signs of hypotension and/or shock. 4 European data show a lifetime prevalence rate of anaphylaxis of around 0.3% (95% confidence interval (CI) 0.1-0.5), while incidence rates for all causes of anaphylaxis range from 1.5 to 7.9 per 100,000 person/year. 5 In children, the incidence of anaphylaxis ranges from 1 to 761 cases per 100,000 person/year. 6 Fatalities due to pediatric anaphylaxis remain relatively low over the last decades in France: between 1979 and 2014, the anaphylaxis mortality rate was 0.077 per million children per year, with a decrease of 7.8% between 1979 and 1985 and 2001-2005. 7 Allergic reactions, including anaphylaxis, are likely to be more frequent in the community. Diagnosis may be challenging, for example, in the absence of an obvious trigger or when symptoms are atypical or rapidly resolving, resulting in an underuse of epinephrine/ adrenaline. 8,9 Early recognition of the reaction and prompt administration of epinephrine/adrenaline remain the cornerstone of the management of anaphylaxis. [1][2][3][4][7][8][9][10] It is now well known that a delayed epinephrine/adrenaline administration (or no administration at all) is associated with increased mortality and a risk of biphasic reactions. 10 Also, an epinephrine/adrenaline auto-injector (EAI), in those countries in which such an option is available, should be prescribed before discharge from the emergency department (ED) to any patient at risk of presenting a further episode of anaphylaxis; also, patients and their caregivers should receive personalized education on its use. 2,3 Despite the existence of national and international guidelines and awareness campaigns on anaphylaxis, epinephrine/adrenaline continues to be underused, 11,12 and antihistamines and corticosteroids are still prescribed as a first line treatment. 13 Several barriers for the appropriate use of epinephrine/adrenaline by physicians in the management of anaphylaxis are suggested, such as a lack of knowledge about epinephrine/adrenaline administration, fear of possible drug-related side effects, misdiagnosis and/or underdiagnosis or, less frequently, over-diagnosis. 12 The present study aimed to assess the appropriateness of epinephrine/adrenaline use in children identified as allergic by physicians in the ED at the time of the reaction, and to identify factors possibly associated with ED epinephrine/adrenaline administration, EAI prescription at discharge, and further referral to an allergist.

| Study design, setting, and population
We conducted a cross-sectional and observational study at the pediatric ED of the University Hospital of Montpellier (France). We included all consecutive children who attended the ED between 2016 and 2020, with an allergy-related discharge diagnosis, based on the tenth revision of the International Classification of Diseases (ICD-10) (Electronic Repository Table A). Patients were excluded if medical records were missing or unavailable.
The study was approved by the Institutional Review Board of Montpellier (IRB-MTP_2021_10_202100955) and registered on ClinicalTrials.gov (NCT05112367).

| Collected data
Besides diagnosis, patients' data were manually extracted through record review by two independent allergists: demographic data, clinical manifestations, previous clinical history with allergic disorder, allergy therapy prescribed during ED access (including possible treatment provided by paramedics/physicians in the ambulance), post-emergency discharge prescriptions and therapeutic education.
As for clinical manifestations, we defined the presence of hypotension as a decrease of 30% of patients' systolic blood pressure compared to the basal value assessed either at their arrival at the ER or on the ambulance before admission. Based on available data, two independent allergists confirmed or not the diagnosis of symptoms possibly related to an allergic reaction and its severity (i.e., anaphylactic, or not) according to the Ring and Messmer classification, 15 adapted 16 and accepted by the WHO, in the ICD-11 classification 17 (Electronic Repository Table B).
Possible disagreement between the two allergists was resolved through discussion with a third specialist to reach a final consensus.
We then differentiated patients presenting with grade I reaction from those with anaphylaxis; we defined as suffering from anaphylaxis only patients presenting with grade II and above symptoms.
All families were contacted by phone to verify if they were referred/consulted an allergist after the acute episode.

| Outcomes of the study
The primary outcome was the appropriateness of epinephrine/ adrenaline injection to children identified as allergic by emergency physicians in the pediatric ED of Montpellier.
The appropriateness assessment was based on the European Academy of Allergy and Clinical Immunology (EAACI) guidelines and the currently accepted international definition of anaphylaxis 2,17-19 : � all patients experiencing anaphylaxis should be treated with epinephrine/adrenaline; � all patients at risk of anaphylaxis are recommended to receive a prescription of EAI; � epinephrine/adrenaline should not be administered to children who do not experience anaphylaxis.
Secondary objectives were to identify factors associated with ED epinephrine/adrenaline administration, EAI prescription, and referral to an allergist in children experiencing anaphylaxis.

| Statistical analysis
Qualitative variables were evaluated as frequencies and percentages, and comparisons of the qualitative data between treated and untreated patients with epinephrine/adrenaline were carried out using chi-square or Fisher's exact test for small samples. Quantitative variables were evaluated as median and interquartile ranges and assessed with the Wilcoxon rank-sum test since they were not normally distributed. Data were considered statistically significant if pvalue was ≤0.05. Univariate and multivariate logistic regression models were used to assess clinical factors associated with ED epinephrine/adrenaline administration, EAI prescription, and referral to an allergist in children experiencing anaphylaxis; odds ratios (ORs) were expressed with 95% CIs. Variables associated with an outcome in the univariate analysis (p-value <0.25) were considered for the multivariate model, and the final model was selected using stepwise regression (p-value <0.05) with Akaike Information Criterion (AIC); discrimination was measured by the area under the curves (AUC).
Correlations between independent variables were also assessed before the selection of the final model. In the multivariable model, both outcome and predictor variables were dichotomized into 'Yes' or 'No' responses, along with the variable "sex" that was dichotomized into 'Female' or 'Male'. All analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC, USA).

| Baseline demographics
Of the 2296 children included and diagnosed using the ICD-10 codes as presenting with an allergic reaction by ED physicians from 2016 to 2020, we confirmed that symptoms were evocative of an allergic reaction only in 1056 patients (46.0%), including 832 patients (78.8%) presenting with grade I hypersensitivity reactions and 224 (21.2%) with anaphylaxis. Concerning these 224 patients, all families answered our phone calls, mainly investigating EAI prescription and allergist referral upon discharge. The Venn diagram shown in Figure 1 describes the study population.
The median age was 53 months for the total population (interquartile range, 20-110 months), and 89 months for children presenting with anaphylaxis (interquartile range, 51-159 months). More than a half of them (53.0% and 57.1%, respectively) were males. 40.2% of children suffering from anaphylaxis reported a history of food allergy. 27.7% consulted during the weekends and 47.3% at night. Other baseline demographic characteristics are listed in Table 1.

| Clinical presentation
The clinical symptoms of the 2296 patients and of the subgroup of 224 children suffering from anaphylaxis are presented in Table 2.
At the ED admission, 185 patients (82.6%) presented with grade II anaphylaxis, and 39 (17.4%) with grade III anaphylaxis. No death from anaphylactic reactions was observed in the included population.
The main presenting symptom, in patients with anaphylaxis, was generalized urticaria, recorded in 168 patients (75.0%).

| Appropriateness of reaction management and discharge
At the emergency room, most children with anaphylaxis were treated with oral antihistamines (72.8%) and oral corticosteroids (61.6%); F I G U R E 1 Patients included in our study, Venn diagram. The total number of patients identifies those with the International Classification of Diseases (ICD-10) diagnosis possibly evocative of an allergic reaction. The two subgroups are composed of children experiencing an allergic reaction and an anaphylactic one, based on an examination of data from their medical charts. intramuscular epinephrine/adrenaline was used in 17.0% of them.
Epinephrine/adrenaline was more frequently prescribed in patients experiencing anaphylaxis with generalized angioedema (39.3% vs. 13.8%, p-value 0.021), or with asthma (34.3% vs. 9.1%, p-value <0.0001). Epinephrine/adrenaline administration was higher for grade III anaphylaxis than for grade II anaphylaxis, even though the T A B L E 1 Characteristics of the included patients.  Comparison between non-anaphylaxis-treated by epinephrine/adrenaline group and non-anaphylaxis-non treated by epinephrine/adrenaline group was performed using the chi2 test or Fisher's exact test and Wilcoxon test. Overall, 28.1% of children with anaphylaxis were discharged with a prescription for an EAI and 50.0% of them received therapeutical education. 57.1% children with anaphylaxis were referred to an allergist after the acute episode. In 35 children not experiencing anaphylaxis (1.7%), an EAI was prescribed at discharge. Figure 2 summarized main outcome results, and Table 3 shows treatment management at ED and at discharge.  Comparison between non-anaphylaxis-treated by epinephrine/adrenaline group and non-anaphylaxis-non treated by epinephrine/adrenaline group was performed using the chi2 test or Fisher's exact test and Wilcoxon test. Factors associated with epinephrine/adrenaline administration, EAI prescription, and referral to an allergist in children with anaphylaxis.
A multivariate logistic regression model was fitted to determine factors that were associated with ED epinephrine/adrenaline administration (

| DISCUSSION
With the rise of allergy incidence and prevalence, especially in Western countries and in children, 6  characterizing these patients, 23 focusing also on the reaction management at the ER. 24 Among the 2296 children evaluated, only 1056 were confirmed as presenting with a (likely) allergic reaction. To evaluate the possible allergic origin of the presented symptoms, each chart was evaluated by two independent allergists, and by a third one in case of disagreement. The fact that 1240 children were excluded from the analysis underlines once again that allergic and hypersensitivity diseases are poorly and not specifically represented in the ICD-10 classification, which was the origin of the need to update this aspect in the ICD-11 version 25 Indeed, diagnosis such as "urticaria (L50-L54)" was included in the original database. Nevertheless, such an unspecific diagnosis in children is often due to non-allergic conditions. Therefore, these children were not correctly classified due not necessarily to a possible misdiagnosis in the ER department, but mainly to the difficulty in classifying them, according to the ICD-10.
As it has been previously shown, 19 Innovation has been brought to our study by identifying factors associated with epinephrine/adrenaline administration, besides severity. 14 Indeed, we showed that clinicians are more prone to administer epinephrine/adrenaline in patients with respiratory symptoms (asthma), generalized angioedema, previous history of food allergy, and grade III anaphylaxis. In our population, age is not associated with under-or over-use, as previously suggested in other studies. 27 Probably, the presence of lower respiratory symptoms T A B L E 3 Treatment administration during emergency and prescription at discharge according to epinephrine/adrenaline administration. Comparison between non-anaphylaxis-treated by epinephrine/adrenaline group and non-anaphylaxis-non treated by epinephrine/adrenaline group was performed using the chi2 test or Fisher's exact test and Wilcoxon test. and/or of generalized edema makes emergency physicians more likely to administer epinephrine/adrenaline in acute settings since they might associate these symptoms with a possible evolution toward fatality. We could also suggest that food allergy, known to be associated with a higher risk of anaphylaxis, could be seen by ED doctors as a risk factor for severe forms and make them more prone to promptly administer the appropriate treatment. Our data cannot explain why in 83.0% of children presenting with anaphylaxis, epinephrine/adrenaline was not administered. This group also unexpectedly included 27 children with anaphylaxis and hypotension. We could simply speculate that anaphylactic symptoms may be interpreted as due to a spectrum of possible differential diagnosis, typical of the pediatric population and that, once again, either anaphylaxis is not promptly diagnosed by non-specialists or that education of allergy symptoms and treatments is still lacking among non-allergist physicians.
Also, as for the acute treatment administration, more than half of the patients with anaphylaxis in our study received corticosteroids and/or antihistamines, which emphasizes that these drugs are still prescribed as first-line treatments in this setting. The overuse of antihistamines and corticosteroids for the acute treatment of anaphylaxis has been found in other studies. 14,[27][28][29][30][31] However, these drugs are not recommended and not effective in anaphylaxis management 2,3,13,[32][33][34] and may delay the administration of epinephrine/adrenaline. Following current guidelines, EAI should be prescribed to all children with a history of anaphylaxis. 2,3 Yet, in our population, only a minority of them (28.1%) were discharged from the ED with such a prescription. In contrast to acute epinephrine/adrenaline administration, the severity of the reaction was not associated with an increase in discharge prescriptions. Several studies have shown higher rates of EAI prescription ranging from 30% to over 90%. 14,35,36 Also, differences have been highlighted when considering a referral to a specialist for a follow-up visit: while this was the case for 57.1% of our patients, data in the literature show percentages ranging from 31.3% to 44.2%. 14,37 Our higher rate can be biased by the fact that we contacted all families systematically by phone to verify such information.
One last aspect that should be pointed out by our results is that even though we state that epinephrine/adrenaline was underused, there were no fatalities in patients presenting with anaphylaxis, and all children were discharged, either at the ER or after hospitalization, with symptoms resolved. There are no solid data on the treatment of anaphylaxis with adrenaline versus placebo, but such a study would not be possible to perform. Further, the severity of a future anaphylactic reaction is difficult to foresee. 38,39 Also, there is insufficient evidence to conclude that adrenaline is lifesaving, especially considering that the baseline risk of anaphylaxis fatality is exceptionally low at baseline if patients receive any treatment. 40 Indeed, one could argue that any hypersensitivity reaction might be self-resolutive (owing to the person own secretion of endogenous natural adrenaline) or be reduced in severity by antihistamines alone, but this hypothesis is merely speculative. From a risk management point of view, considering the mechanisms of action of the drug and of the immunological reaction, it is still to be considered as a safer and the best recommended option to promptly treat any anaphylactic reaction with adrenaline.
Our study presents some limitations. First, being a retrospective cross-sectional study, certain clinical information could be missing from the medical record, even after contacting the families by phone.
Moreover, our work is based on data from a single center; the generalizability of the results should be examined via additional multicenter and/or longitudinal studies. Also, we retrospectively classified hypersensitivity allergic reactions following Ring and Messmer's classification and many other different classifications have been proposed after the cited one. Even though this classification was initially applied to drugs hypersensitivity reactions, it has been widely used since its original publication to classify severity reactions from any type of allergen. In our cohort, we did not focus on the type of allergen eliciting the symptoms. Therefore, we preferred to use Messmer's method since it is widely accepted, even though it could score for a milder severity score in food allergy compared to Sampson's classification. 41 Moreover, this classification aligns with the current definition of anaphylaxis proposed by the WHO classification ICD-11. 16 Finally, a high rate of non-allergic reactions (54.0%) was also reported in our study, underlining the limitations of the use of administrative codes (ICD-10), which might lead to misclassification and misdiagnosis. 42 The currently deployed version of ICD (ICD-11) now includes "Allergic and hypersensitivity conditions" section (in the "Immune System Diseases" chapter) 16,17 , which will allow a more accurate diagnosis and follow-up of anaphylaxis.
In conclusion, the present study helps better understand how anaphylaxis is managed at the emergency room in children based on real-life data and fills the gaps in current knowledge. We demonstrated the need to strengthen local and/or regional training on anaphylaxis management and dissemination of current guidelines to emergency physicians to promptly administer the adapted therapy,

ACKNOWLEDGMENTS
The study received no funding.

CONFLICT OF INTEREST STATEMENT
The authors declare no potential conflicts of interest for the present paper.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.